Inclusion complexes of aryl-heterocyclic salts

ABSTRACT

Compositions of matter comprising a pharmaceutically acceptable salt of an aryl-heterocyclic compound, such as ziprasidone, in a cyclodextrin. Preferred cyclodextrins are SBECD and HPBCD. The composition can comprise a dry mixture, a dry inclusion complex or an aqueous solution. The salt/cyclodextrin inclusion complex preferably provides an amount of ziprasidone of at least 2.5 mgA/ml when the complex is dissolved in water at 40% w/v. A variety of ziprasidone salts are preferred, including the mesylate, esylate, besylate, tartrate, napsylate, and tosylate.

This is a National Stage filing under 35 USC §371 based onPCT/IB97/00321 which was filed internationally on Apr. 1, 1997 and whichclaimed priority from U.S. provisional application No. 60/019,204 filedMay 7, 1996.

FIELD OF THE INVENTION

This invention relates to compositions comprising a salt of anarylpiperazinyl-C₂ or -C₄ alkyleneheterocycle and a cyclodextrin.

BACKGROUND OF THE INVENTION

Formulation of pharmaceutical dosage forms is frequently hampered bypoor aqueous solubility and/or stability of the drug of interest, whichin turn can severely limit its therapeutic application. Conversely,increasing drug solubility and stability through appropriate formulationcan accordingly lead to increased therapeutic efficacy of the drug.Various methods have been used to increase the solubility and stabilityof drugs such as the use of organic solvents, emulsions, liposomes andmicelles, adjustments to pH and the dielectric constant of formulationssolvent systems, chemical modifications, and complexation of the drugswith appropriate complexing agents such as cyclodextrins.

Cyclodextrins, sometimes referred to as Schardinger's dextrins, werefirst isolated by Villiers in 1891 as a digest of Bacillus amylobacteron potato starch. The foundations of cyclodextrin chemistry were laiddown by Schardinger in the period 1903-191 1. Until 1970, however, onlysmall amounts of cyclodextrins could be produced in the laboratory andthe high production cost prevented the usage of cyclodextrins inindustry. In recent years, dramatic improvements in cyclodextrinproduction and purification have been achieved and cyclodextrins havebecome much less expensive, thereby making the industrial application ofcyclodextrins possible.

Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on theouter surface and a void cavity in the center. Their outer surface ishydrophilic, and therefore they are usually soluble in water, but thecavity has a lipophilic character. The most common cyclodextrins areα-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, consisting of 6; 7and 8 α-1,4-linked glucose units, respectively. The number of theseunits determines the size of the cavity.

Cyclodextrins are capable of forming inclusion complexes with a widevariety of hydrophobic molecules by taking up a whole molecule (a “guestmolecule”), or some part of it, into the void cavity. The stability ofthe resulting complex depends on how well the guest molecule fits intothe cyclodextrin cavity. Common cyclodextrin derivatives are formed byalkylation (e.g., methyl-and-ethyl-β-cyclodextrin) or hydroxyalkylationof the hydroxyethyl-derivatives of α-, β-, and γ-cyclodextrin) or bysubstituting the primary hydroxyl groups with saccharides (e.g.,glucosyl- and maltosyl-β-cyclodextrin). Hydroxypropyl-β-cyclodextrin andits preparation by propylene oxide addition to β-cyclodextrin, andhydroxyethyl-β-cyclodextrin and its preparation by ethylene oxideaddition to β-cyclodextrin, were described in a patent of Gramera et al.(U.S. Pat. No. 3,459,731, issued August 1969) over 20 years ago.

Although cyclodextrins have been used to increase the solubility,dissolution rate and/or stability of a great many compounds, it is alsoknown there are many drugs for which cyclodextrin complexation either isnot possible or yields no advantages. See J. Szejtli, Cyclodextrins inDrug Formulations: Part II, Pharmaceutical Technology, 24-38, August,1991.

It is conventionally believed that a salt of a drug dissolves in acyclodextrin-containing aqueous medium by simply dissociating to form acharged drug molecule and a counter-ion, and that it is the dissociated(charged) drug molecule which acts as a guest moiety and forms inclusioncomplexes with the cyclodextrin. A consequence of this is the beliefthat there are no differences in equilibrium solubility among the saltsof a given drug in a specific cyclodextrin. Thus, if a solubility-phasediagram is generated for a particular drug in a particular aqueouscyclodextrin (i.e., a plot of the equilibrium solubility of a drug saltin the aqueous cyclodextrin as a function of cyclodextrinconcentration), different salts of the drug should plot out as lineshaving the same slope.

The present invention is based, inter alia, on the determination thatthe solubility of the compounds presented below form stable inclusioncomplexes with cyclodextrins, and that such inclusion complexes arehighly water soluble relative to the non-complexed drug.

The present invention is further based on the unexpected and surprisingdiscovery that, in a particular cyclodextrin, there are solubilitydifferences among particular salts of the aryl-heterocyclics usefulherein. A particular salt of a specific aryl-heterocyclic can exhibitmuch greater solubility in a particular aqueous cyclodextrin solutionthan a different salt of the same aryl-heterocycle in the samecyclodextrin. Some salts show unexpectedly high solubility. Many, if notall, of the salts investigated for this invention exhibited their owndistinctive slope when plotted on a solubility-phase diagram.

In the particular case of the aryl-heterocyclic ziprasidone, it has beendetermined that the order of solubility (e.g., the increasing order ofsolubility) of a series of different ziprasidone salts in aqueouscyclodextrin solution does not necessarily correlate with the order ofsolubility of those same salts in water.

SUMMARY OF THE INVENTION

In one embodiment this invention provides compositions of mattercomprising a cyclodextrin and a pharmaceutically acceptable salt of acompound (herein referred to as an “aryl-heterocyclic”) having theformula

wherein

Ar is benzoisothiazolyl or an oxide or dioxide thereof each optionallysubstituted by one fluoro, chloro, trifluoromethyl, methoxy, cyano, ornitro;

n is 1 or 2; and

X and Y together with the phenyl to which they are attached formbenzothiazolyl; 2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl;3-hydroxyindazolyl; indolyl; oxindolyl optionally substituted by one tothree of (C₁-C₃)alkyl, or one of chloro, fluoro or phenyl, said phenyloptionally substituted by one chloro or fluoro; benzoxazolyl;2-aminobenzoxazolyl; benzoxazolonyl; 2-aminobenzoxazolinyl;benzothiazolonyl; benzoimidazolonyl; or benzotriazolyl. The precedingcompounds are disclosed in U.S. Pat. No. 4,831,031, herein incorporatedby reference in its entirety.

A preferred subgroup of the above compositions is the subgroup wherein Xand Y together with the phenyl to which they are attached form oxindole;A preferred subgroup within this subgroup occurs when the oxindolemoiety is 6-chlorooxindole-5-yl.

A further preferred subgroup of compositions is the subgroup wherein Aris benzoisothiazolyl.

A further preferred subgroup of compositions is the subgroup wherein nis 1.

A preferred aryl-heterocyclic is ziprasidone, which has the structure

It is also disclosed in the previously mentioned U.S. Pat. No.4,831,031, has utility as a neuroleptic, and is thus useful as anantipsychotic.

Further preferred compositions of matter comprise a pharmaceuticallyacceptable salt of ziprasidone and a cyclodextrin,

wherein said salt is selected from the tosylate, tartrate, napsylate,besylate, aspartate, esylate and mesylate salt;

and wherein said cyclodextrin is selected from γ-cyclodextrin, SBECD andHPBCD.

This invention thus provides compositions of matter comprising apharmaceutically acceptable salt of an aryl-heterocyclic and acyclodextrin. The compositions can be administered orally, for exampleas a tablet or capsule, or parenterally, for example, as an injectableor by inhalation to a mammal in need thereof.

The phrase “composition(s) of matter” as used herein including theappendant claims encompasses, inter alia, compositions of anaryl-heterocyclic and a cyclodextrin which are dry physical mixtures,which are dry inclusion complexes, and which are aqueous solutions ofdissolved inclusion complexes. For example, a composition can comprise adry mixture of an aryl-heterocyclic physically mixed with a drycyclodextrin. A composition, in a preferred embodiment, can alsocomprise an aqueous solution which has been lyophilized or otherwisedried (e.g., in a vacuum oven or other suitable device), such that thecomposition comprises a dry, pre-formed inclusion complex ofcyclodextrin-complexed aryl-heterocyclic which can later bere-constituted. A composition can also comprise the aqueous solutionitself, i.e., an aryl-heterocyclic plus cyclodextrin plus water.Inclusion complexes are thus within the scope of the term “compositionof mafter” whether they are pre-formed, formed in situ, or formed invivo.

The aryl-heterocyclic salt is advantageously relatively highly solublein aqueous cyclodextrin solution, and if administered to a patientparenterally as an aqueous solution, can accordingly be administered ina relatively small injection volume.

Physical mixtures of a cyclodextrin and an aryl-heterocyclic areusefully employed and are within the scope of this invention. A mixtureof a cyclodextrin and an aryl-heterocyclic, for example used as fill fora capsule or compressed into a tablet for oral administration, will forman inclusion complex on exposure to an aqueous environment of use suchas the luminal fluid of the gastrointestinal tract or the salivary fluidof the buccal cavity, and thereby aid in increasing bioavailabilityrelative to the uncomplexed drug. Cyclodextrin can be present in anamount over that needed to complex the drug completely since extracyclodextrin aids in dissolution of the dosage form once it contactsaqueous fluid.

In a further aspect, this invention provides compositions of mattersuitable for administration to a human patient as a solution (e.g., asan injectable or intranasally), comprising an inclusion complex of asalt of ziprasidone in a cyclodextrin. Advantageously, in a preferredembodiment said inclusion complex provides an amount of ziprasidone ofat least 2.5 mgA/ml when the amount of ziprasidone (or otheraryl-heterocyclic) provided by said complex is measured at acyclodextrin concentration of 40% w/v in water.

Inclusion complexes that provide at least 10 mgA/ml of ziprasidone at40% w/v in water are more preferred.

Inclusion complexes that provide at least 15 mgA/ml of ziprasidone at40% w/v are most preferred.

As a further feature of the invention, the mesylate, esylate, andtartrate salts of ziprasidone are provided.

The phrase “mgA” indicates the weight (in mg) of ziprasidone (or otheraryl-heterocyclic) calculated as the free base, (for ziprasidone,molecular weight=412.9).

The phrase “measured at a cyclodextrin concentration of 40% w/v inwater” as used above and in the claims provides a standard against whichthe degree of solubility of a particular inclusion complex ofziprasidone in a particular cyclodextrin, and hence its usefulness, canbe compared. The phrase is not to be interpreted as limiting theinvention in any way. For example, assume that a test solution of aparticular cyclodextrin X in water is made up to 40% w/v (“w/v” beingbased, of course, on the weight “w” of the cyclodextrin in water, “v”referring to the total solution volume), and that this test solution, atequilibrium solubility, provides a concentration of 10 mgA/ml ofziprasidone salt Y. The (dry or non-solvated) inclusion complex (i.e.,of ziprasidone salt Y in cyclodextrin X) used to make the 40% testsolution thus represents a preferred inclusion complex because itexceeds the standard of 2.5 mgA/ml. Assuming that the solubility phasediagram for ziprasidone salt X is linear and passes through the origin,an inclusion complex of salt Y in the same cyclodextrin X, for exampleat an aqueous cyclodextrin concentration of 20% w/v, will provide 5mgA/ml. The inclusion complex used to make this second solution isequally preferred even though a different concentration of cyclodextrinin water was employed to make the ziprasidone salt solubilitymeasurement.

Viewed alternatively, an aqueous cyclodextrin test concentration of 40%w/v provides a point at which a determination can be made regardingwhether a cyclodextrin inclusion complex of a particular ziprasidonesalt in a particular cyclodextrin can provide at least 2.5 mgA/ml ofziprasidone. If such determination is positive, any inclusion complexmade with that salt and that cyclodextrin is preferred.

Use of the term “salt” herein, including the appendant claims, shall beunderstood to refer to pharmaceutically acceptable acid addition saltsof aryl-heterocyclics, including ziprasidone. The salts employed can beanhydrous or in the form of one or more solvates, such as hydrates,including mixtures thereof. The salts may occur in different polymorphicforms. For example, co-pending U.S. provisional application No.60/016537, herein incorporated by reference, discloses the mesylatetrihydrate salt of ziprasidone. Co-pending U.S. provisional applicationNo. 60/016757, herein incorporated by reference, discloses the mesylatedihydrate salt of ziprasidone.

“Product solution” as used herein, including the appendant claims, meansan aqueous solution of a salt of an aryl-heterocyclic (includingziprasidone) inclusion complex in a cyclodextrin, which solution ispharmaceutically acceptable and ready for administration to a patient.

The fact that different aryl-heterocyclic salts can exhibit differingsolubilities in a particular aqueous cyclodextrin solution is applicableto cyclodextrins in general, including those which are presently known.Useful cyclodextrins include α, β, and γ cyclodextrins, methylatedcyclodextrins, hydroxypropyl-β-cyclodextrin (HPBCD),hydroxyethyl-β-cyclodextrin (HEBCD), branched cyclodextrins in which oneor two glucoses or maltoses are enzymatically attached to thecyclodextrin ring, ethyl- and ethyl-carboxymethyl cyclodextrins,dihydroxypropyl cyclodextrins, and sulfoalkyl ether cyclodextrins. Thedegree of substitution is not considered to be critical, and thecyclodextrins just mentioned can have essentially any degree ofsubstitution (per entire cyclodextrin molecule) as known in the art.Mixtures of cyclodextrins, as well as single species, are feasible formaking dosage forms according to the invention.

β-cyclodextrin sulfobutyl ether(SBECD), hydroxypropyl β-cyclodextrin(HPBCD), and γ-cyclodextrin are preferred for use in this invention.HPBCD and SBECD are preferred for parenteral administration. For oraladministration γ-cyclodextrin is preferred. HPBCD is well known in theart, see for example Publication R 81 216 entitled “Encapsin HPB” fromJanssen Biotech N.V. SBECD is also known and has been disclosed in U.S.Pat. Nos. 5,376,645 and 5,134,127, both to Stella et al. and both hereinincorporated by reference in their entirety.

A preferred group of inclusion complexes of ziprasidone salts includes

(1) the tosylate, napsylate, besylate, aspartate, tartrate, esylate(ethanesulfonate) or mesylate (methanesulfonate) salts of ziprasidone,each complexed with SBECD; and

(2) the tartrate, esylate, or mesylate salts of ziprasidone, eachcomplexed with HPBCD.

A more preferred group of inclusion complexes of ziprasidone saltsincludes

(1) the tosylate, napsylate, besylate, tartrate, esylate or mesylatesalts of ziprasidone, each complexed with SBECD; and

(2) the tartrate, esylate, or mesylate salts of ziprasidone, eachcomplexed with HPBCD.

A still more preferred group of inclusion complexes of ziprasidone saltsincludes

(1) the tartrate, esylate, or mesylate salts of ziprasidone, eachcomplexed with SBECD; and

(2) the tartrate, esylate or mesylate salts of ziprasidone, eachcomplexed with HPBCD.

A still more preferred group of inclusion complexes of ziprasidone saltsinclude ziprasidone mesylate or tartrate, each complexed with SBECD

Most preferred is ziprasidone mesylate complexed with SBECD.

The inclusion complexes of this invention can be administered orally andparenterally, as previously noted.

As previously noted, this invention is based, inter alia, on thedetermination that, for a particular cyclodextrin, the solubility of anaryl-heterocyclic salt such as a ziprasidone salt in that cyclodextrinis dependent on the particular salt employed. That is, differentaryl-heterocyclic salts, including ziprasidone, exhibit (sometimeswidely) differing solubilities in the same cyclodextrin. This phenomenonof variable solubility is particularly important for parenteraladministration because it allows for increasing the loading of anaryl-heterocyclic in a cyclodextrin by selecting a salt with relativelyhigh cyclodextrin solubility. Increased loading in turn allows for thecapability of parenterally delivering a given dose of aryl-heterocyclicin a relatively decreased injection volume. Viewed alternatively, sincethe weight of cyclodextrin required to dissolve a given weight of anaryl-heterocyclic decreases with increasing salt solubility in anaqueous solution of the cyclodextrin, and assuming a constant loading ofziprasidone, injection volume can be reduced by choosing an appropriate,highly soluble salt. It is well known in the medical arts that pain oninjection can increase in proportion to the injection volume employed.Patient compliance with parenteral administration can be affectedaccordingly. Thus the ability to administer ziprasidone in a decreasedinjection volume represents a significant advance in this art. Forexample, in many cases, this invention provides therapeutic solutions ofa ziprasidone inclusion complex which provide the maximum once-dailylevel of ziprasidone in a single injection volume less than 2 ml.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a solubility phase diagram which is a plot of the maximumequilibrium solubility of a series of ziprasidone salts as a function ofSBECD concentration in water.

The ordinate (Y-axis) is Drug Solubility (units are millimolar) and theabscissa (X-axis) is SBECD concentration (also millimolar units).

The symbology employed is explained in the following chart:

Salt + Mesylate X Tartrate Δ Esylate • Napsylate ∘ HCI

DETAILED DISCUSSION

The amount of aryl-heterocyclic to be administered to a patient is aneffective amount, generally from 5 to 500 mgA, in single or divideddoses, orally or parenterally. The specific dose administered willdepend on the particular condition being treated. With respect toziprasidone specifically, a recommended range for oral dosing is 5-300mgA/day, preferably 40-200 mgA/day, more preferably 40-80 mgA in singleor divided doses. A generally recommended therapeutic range foradministering ziprasidone parenterally by injection is 2.5 mgA/day to160 mgA/day, preferably 5-80 mgA/day depending on several factors suchas the size and condition of the patient. The ability to generate anaqueous cyclodextrin complex which provides at least 2.5 mgA/ml ofziprasidone means that the lower end of the above parenteral therapeuticranges (2.5 mgA/day and 5 mgA/day) can be met by a single or by adivided, twice-per-day dose, with each administration comprising aninjection of 1 ml at 2.5 mgA/ml. It will be demonstrated below that theinvention provides inclusion complexes with the ability to deliver muchgreater concentrations of ziprasidone as well.

The amount of cyclodextrin used in a particular formulation is abioavailability-increasing amount. Small amounts of cyclodextrin evenwhen present in a dosage form which is a mixture, can enhancebioavailability by forming an inclusion complex in vivo. Generally theamount of cyclodextrin in a formulation is such that the molar ratio ofcyclodextrin to drug is between 0.1:1 and 100:1, preferably between0.25:1 and 10:1, more preferably between 0.5:1 and 5:1. If theformulation is an aqueous solution, it can contain cyclodextrin in awide range of concentrations, e.g., from 5 wgt % (w/v) to over 100 wgt %(w/v). At high concentrations of cyclodextrins, formulations becomesomewhat viscous and are amenable to oral administration as elixirs orsyrups.

The invention, as previously mentioned, is applicable toaryl-heterocyclics of formula I, as previously defined. For convenience,however, the following discussion is directed to ziprasidone as arepresentative member of the class of aryl-heterocyclics. Those skilledin the art will of course recognize that the teachings with respect toziprasidone are applicable to the other members of the class as well.

The pharmaceutically acceptable acid addition salts of ziprasidone canbe prepared as known in the art by conventional methodology by treatinga solution or suspension of ziprasidone free base with about onechemical equivalent or a slight excess of a pharmaceutically acceptableacid. The salt can be isolated by conventional methods, such as byfiltration when the salt spontaneously precipitates, e.g., as acrystalline material or, particularly if the salt is amorphous, it canbe isolated by concentration and/or addition of a non-solvent. Forexample, the salts employed in this invention were made by firstweighing an amount of ziprasidone free base and adding it to a solvent,typically tetrahydrofuran (THF), water, a lower alcohol, or a mixture oftwo or more solvents. The solvent(s) used can depend on whether it isdesired to isolate the salt from a slurry or from a solution. If it isdesired to isolate the salt from a solution, the solvent can be heated,with stirring, to between 60 and 70° C. to facilitate dissolution. Thenabout one molar equivalent of an acid, or a slight excess (usually up to1.5:1, acid:base) corresponding to the desired counterion is added withstirring. Heating is maintained, usually for about two hours or longer,and then the solution is allowed to cool to room temperature for severalhours, typically overnight, while stirring is maintained. The solids canthen be harvested by filtration and washed with the cooled solventcomposition.

An inclusion complex of a pharmaceutically acceptable acid addition saltof ziprasidone can be formed conventionally by known methodology. Thatis, a desired inclusion complex of a pharmaceutically acceptableziprasidone salt can be formed in situ by adding a ziprasidone salt, inan amount up to the amount corresponding to its equilibrium solubilty(or less depending on the desired strength of the product solution),directly to a pre-made solution of cyclodextrin dissolved in water (orother suitable pharmaceutically acceptable aqueous medium). Acombination comprising water (or other pharmaceutically acceptableaqueous medium such as a buffer), cyclodextrin, and a ziprasidone saltdissolved therein is sufficient to form a product solution which can beparenterally administered directly to human patients. A product solutionmade with sterile water can be used as is for administration to patientsimmediately, no adjustment to isotonicity being required, or stored at5° C. for periods up to two years and longer.

Alternatively, the inclusion complex of ziprasidone in cyclodextrin canfirst be isolated by drying, usually by lyophilization. The isolated dryinclusion complex can be stored at room temperature for periods up totwo years and longer, and reconstituted into a product solution asneeded. When a product solution is required, it can be made bydissolving the isolated inclusion complex in water (or other aqueousmedium) in an amount sufficient to generate a solution of the requiredstrength for oral or parenteral administration to patients. Ifparenteral administration is the chosen route of administration,intramuscular injection is preferred.

Solubility testing of various ziprasidone salts in, as examplecyclodextrins, SBECD and HPBCD, was conducted by comparing theequilibrium solubility of each salt in an equal amount of aqueouscyclodextrin. Many different experimental protocols can be envisionedand implemented. The following protocol illustrates the protocolemployed for the instant invention using 40% aqueous cyclodextrin. Thesame protocol was employed for other aqueous cyclodextrin concentrationssuch as those used to generate FIG. 1. HPBCD was purchased commerciallyfrom Wacker Chemie. The SBECD employed had a degree of substitution withsulfobutyl groups of 6.5, average, per molecule of β-cyclodextrin, madeby a process along the lines of that described in Example 3 of U.S. Pat.No. 5,376,645.

A 40% (w/v) solution of cyclodextrin (SBECD or HPBCD) in water wasprepared by adding 200 g of cyclodextrin to a 500 ml beaker containingapproximately 250 ml of deionized water and a magnetic stir bar. Thecontents were stirred until dissolution of the cyclodextrin in the waterwas complete, usually a time of about one hour being sufficient. Thesolution was then transferred to a 500 ml volumetric flask and deionizedwater was added to the mark. 5 ml of the volumetric solution waspipetted into a 10 ml glass vial with a screw cap. An excess of thesolid ziprasidone salt test candidate and a magnetic stir bar were addedto the vial. The vial contents were stirred for four days at ambienttemperature to allow a sufficient time for equilibrium to beestablished. Upon removal from the magnetic stirrer, the sample hadundissolved solid present, indicating a saturated solution under theconditions employed. The contents were filtered into a clean screw capvial through a Millex-GS 0.2 μm filter and the drug concentrationdetermined by an HPLC method.

As an example of an HPLC assay to determine ziprasidone solubility, theamount of dissolved ziprasidone can be determined by using a C18 Puresil(Registered Trademark of Waters Associates) column with an isocraticmobile phase consisting of 60% 0.05M potassium dihydrogen phosphatebuffer and 40% methanol, at a flow rate of 2 ml/min at 40° C. Detectioncan be by UV absorption at a wavelength of 229 nm. Quantification can beeffected facilely by comparison of HPLC peak height (or area) with thepeak height (or area) taken from a standard plot of concentration vs.peak height (or area) for standards of known concentration. As isconventional, the ziprasidone standard concentrations are selected tofall within a linear range of concentration vs absorbance for the UVdetector employed. The saturated equilibrium solution obtained afterfiltering the vial test solution may need to be diluted in serialfashion to reach the linear range of the standard plot, and dilution canbe effected by adding isocratic mobile phase.

The above procedure was also employed to determine the equilibriumsolubility of ziprasidone salts in other concentrations of cyclodextrin.By doing this and using the data to make solubility phase diagrams fordifferent ziprasidone salts, it was determined that the solubility phasediagrams were linear for each salt, but that the slopes were different,thereby demonstrating that different ziprasidone salts can havedifferent equilibrium solubilities in the same cyclodextrin solution.The solubility phase diagram generated by doing this for differentziprasidone salts is shown in FIG. 1.

Using the above HPLC procedure (including the column and isocraticmobile phase) a number of ziprasidone salts were tested to determine theequilibrium solubility of each in 40% HPBCD and in 40% SBECD. Resultsare reported in Table 1.

TABLE I Solubility of ziprasidone salts in water and 40% cyclodextrinsolutions. Solubility Solubility in 40% Solubility in 40% Salt form inwater HPBCD SBECD free base 0.3 μA/ml  0.26 mgA/ml 0.35 mgA/ml tosylate5 μA/ml NT 14 mgA/ml napsylate 34 μA/ml NT 14 mgA/ml besylate 80 μA/mlNT 12 mgA/ml hydrochloride 80 μA/ml  2.4 mgA/ml 4 mgA/ml aspartate 170μA/ml  1.3 mgA/ml 9.3 mgA/ml tartrate 180 μA/ml 12.4 mgA/ml 26 mgA/mlesylate 360 μA/ml 13.7 mgA/ml 15 mgA/ml mesylate 1000 μA/ml 17.3 mgA/ml44 mgA/ml Note: μgA and mgA indicate the weight (in μg or mgrespectively) of ziprasidone calculated as the free base, Molecularweight = 412.9; NT = Not tested Molecular weight of β-cyclodextrinsufobutyl ether (SBECD): 2163; 40% (w/v) = 400 g/L = 0.18 M; Molecularweight of hydroxy propyl β-cyclodextrin (HPBCD): 1309; 40% (w/v) = 400g/L = 0.31 M

Table 1 indicates that for the particular ziprasidone salt candidatesand cyclodextrin solutions tested, the highest solubility of ziprasidonecan be achieved by dissolving ziprasidone mesylate in 40% SBECD. Todeliver a therapeutic dose of ziprasidone, for example, of 80 mg/day ofziprasidone to a patient, for example by injection, the volume of 40%solution needed can be calculated as follows:

80 mgA/day×1 ml/44 mgA=1.8 ml/day

Thus the instant invention provides therapeutically useful ziprasidonesalt inclusion complexes. That is inclusion complexes which deliver adesired therapeutic dose of ziprasidone in an injection volume of lessthan 2 ml, can be determined.

As seen from FIG. 1, ziprasidone salt solubility is linear as a functionof cyclodextrin concentration in water. Thus the maximum amount of aparticular ziprasidone salt which can be dissolved in an aqueouscyclodextrin can be measured as known in the art directly from such asolubility phase diagram (i.e., employing the appropriate line as acalibration plot), or calculated if the slope (and y-intercept, if it isnon-zero) of the appropriate line has been computed.

As previously mentioned, the inclusion complex can be formulated fororal or for parenteral administration, usually intramuscularadministration, to a patient. Subcutaneous, intravenous and intranasaladministration is also feasible. If necessary to adjust isotonicity, itcan be accomplished conventionally by adding an isotonicity adjustingagent. Product solutions, as previously defined, can be used directlyfor parenteral administration. Dry mixtures of ziprasidone pluscyclodextrin can be sold as a unit dose packet for use by dissolution inwater for oral administration. Dry mixtures of ziprasidone pluscyclodextrin, plus a dry filler if needed, can be used as fill formaking capsules. Mixtures of ziprasidone plus cyclodextrin, optionallyplus excipients such as binders, fillers, and lubricants, as known inthe art, can be conventionally used to make tablets with conventionalpresses.

The following examples further disclose and illustrate the invention:

EXAMPLE 1

A 300 mg/ml SBECD solution is prepared by dissolving SBECD in apharmaceutically acceptable aqueous medium such as water. Ziprasidonemesylate is dissolved in the SBECD solution to make a concentration of27.3 mg/ml (20 mgA/ml). The solution is sterile filtered through a 0.2μm filter. Glass vials are filled with the filtered solution to make aproduct solution which can be administered orally or by anintramuscular, intravenous, or subcutaneous route.

EXAMPLE 2

A product solution is made as described in Example 1. Glass vialscontaining product solution are loaded into a freeze dryer and theproduct solution is freeze dried. The vials and their lyophilizedcontents are stored at room temperature until needed, at which time theyare reconstituted with sterile water or a pharmaceutically acceptableaqueous buffer for administration orally or by an intramuscular,intravenous, or subcutaneous route.

The following examples illustrate how to calculate dosage levels forparticular inclusion complexes to deliver a particular dose, and alsohow to minimize injection volume.

EXAMPLE 3

Formulation I: Ziprasidone Mesylate 40 mgA/ml in 40% (w/v) SBECD

Table 1 indicates that for a 20 mgA dose, about 0.5 ml of solutionshould be injected. For a maximum dose, 1.8 ml should be injected.

EXAMPLE 4

Formulation II: Ziprasidone Tartrate 20 mgA/ml in 40% (w/v) SBECD

For a 20 mgA dose, 0.8 ml of solution should be injected.

For a 40 mgA dose, 1.5 ml of solution should be injected.

For a 60 mgA dose, 2.3 ml of solution should be injected.

EXAMPLE 5

Ziprasidone Mesylate

1 g of ziprasidone free base was added to 20 mL of isopropyl alcohol,followed by 140mg of methanesulfonic acid. After a few minutes theslurry which formed thickened and lightened somewhat in color as itprecipitated. The salt was harvested by filtration through a 5 μmpolytetrafluoroethylene membrane.

EXAMPLE 6

Ziprasidone Esylate

1 g of ziprasidone free base was added to 45 mL of THF and 1 mL ofwater, and the mixture was heated to 60° C. while stirring. The mixturewas maintained at 60° C. for two hours, at which time all of the freebase had dissolved. 156 mg of ethanesulfonic acid was added and stirringwas maintained at 60° C. for two more hours. The mixture turned fromlight orange to hazy during this time, at which point heating wasstopped and the salt started to precipitate. The mixture was allowed tocool to room temperature overnight while stirring continued. The saltwas then harvested by filtration as in Example 5.

EXAMPLE 7

Ziprasidone Tartrate

1 g of ziprasidone free base was added to 60 mL of water and theresulting slurry was heated to 50° C. for 3 hours with stirring. 900 mgof L-tartaric acid was added. Heating at 50° C. and stiring werecontinued for 6 more hours, and then the mixture was stirred at 40° C.overnight. The solution was then allowed to cool and the salt harvestedas in Example 5.

What is claimed is:
 1. A composition of matter comprising apharmaceutically acceptable salt of a compound of the formula

and a cyclodextrin, wherein Ar is benzoisothiazolyl or an oxide ordioxide thereof each optionally substituted by one fluoro, chloro,trifluoromethyl, methoxy, cyano, or nitro; n is 1 or 2; and X and Ytogether with the phenyl to which they are attached form benzothiazolyl;2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 3-hydroxyindazolyl;indolyl; oxindolyl optionally substituted by one to three of(C₁-C₃)alkyl, or one of chloro, fluoro or phenyl, said phenyl optionallysubstituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl;benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl;benzoimidazolonyl; or benzotriazolyl.
 2. A composition as defined inclaim 1, comprising a dry mixture of said compound and saidcyclodextrin.
 3. A composition as defined in claim 1, comprising a dryinclusion complex of said compound complexed with said cyclodextrin. 4.A composition as defined in claim 1, comprising an aqueous solution ofan inclusion complex of said drug complexed with said cyclodextrin.
 5. Acompositon as defined in claim 1, wherein X and Y together with thephenyl to which they are attached form oxindole.
 6. A composition asdefined in claim 1, wherein Ar is benzoisothiazolyl.
 7. A composition asdefined in claim 1, wherein n is
 1. 8. A composition as defined in claim1, wherein said compound is ziprasidone.
 9. A composition as defined inclaim 1, wherein said cyclodextrin is selected from γ-cyclodextrin,HPBCD and SBECD.
 10. A composition as defined in claim 9, wherein saidcyclodextrin is selected from HPBCD and SBECD.
 11. A composition ofmatter comprising an inclusion complex of a pharmaceutically acceptablesalt of a compound of the formula

in a cyclodextrin, wherein Ar is benzoisothiazolyl or an oxide ordioxide thereof each optionally substituted by one fluoro, chloro,trifluoromethyl, methoxy, cyano, or nitro; n is 1 or 2; and X and Ytogether with the phenyl to which they are attached form benzothiazolyl;2-aminobenzothiazolyl; benzoisothiazolyl; indazolyl; 3-hydroxyindazolyl;indolyl; oxindolyl optionally substituted by one to three of(C₁-C₃)alkyl, or one of chloro, fluoro or phenyl, said phenyl optionallysubstituted by one chloro or fluoro; benzoxazolyl; 2-aminobenzoxazolyl;benzoxazolonyl; 2-aminobenzoxazolinyl; benzothiazolonyl;benzoimidazolonyl; or benzotriazolyl.
 12. A compositon as defined inclaim 11, wherein X and Y together with the phenyl to which they areattached form oxindole.
 13. A composition as defined in claim 11,wherein Ar is benzoisothiazolyl.
 14. A composition as defined in claim11, wherein n is
 1. 15. A composition as defined in claim 11, whereinsaid compound is ziprasidone.
 16. A composition as defined in claim 11,wherein said cyclodextrin is selected from γ-cyclodextrin, HPBCD, andSBECD.
 17. A composition as defined in claim 16, wherein saidcyclodextrin is selected from HPBCD and SBECD.
 18. A composition ofmatter comprising an inclusion complex of a pharmaceutically acceptablesalt of ziprasidone in a cyclodextrin.
 19. A composition as defined inclaim 18, wherein said cyclodextrin is selected from HPBCD and SBECD.20. A composition of matter comprising an inclusion complex of apharmaceutically acceptable salt of ziprasidone in a cyclodextrin, saidinclusion complex providing an amount of ziprasidone of at least 2.5mgA/ml when the amount of ziprasidone provided by said complex ismeasured at a cyclodextrin concentration of 40% w/v in water.
 21. Acomposition as defined in claim 20, wherein said cyclodextrin isselected from SBECD and HPBCD.
 22. A composition as defined in claim 20,wherein said amount of ziprasidone is at least 10 mgA/ml.
 23. Acomposition as defined in claim 22, wherein said amount of ziprasidoneis at least 15 mgA/ml.
 24. A composition as defined in claim 21, whereinsaid inclusion complex is selected from (1) the tosylate, napsylate,besylate, aspartate, tartrate, esylate and mesylate salts ofziprasidone, each complexed with SBECD; and (2) the tartrate, esylate,and mesylate salts of ziprasidone, each complexed with HPBCD.
 25. Acomposition as defined in claim 24, wherein said inclusion complex isselected from (1) the tosylate, napsylate, besylate, tartrate, esylateand mesylate salts of ziprasidone, each complexed with SBECD; and (2)the tartrate, esylate, and mesylate salts of ziprasidone, each complexedwith HPBCD.
 26. A composition as defined in claim 25, wherein saidinclusion complex is selected from (1) the tartrate, esylate, andmesylate salts of ziprasidone, each complexed with SBECD; and (2) thetartrate, esylate and mesylate salts of ziprasidone, each complexed withHPBCD.
 27. A composition as defined in claim 26, wherein said inclusioncomplex is selected from ziprasidone mesylate and tartrate, eachcomplexed with SBECD.
 28. A composition as defined in claim 27, whereinsaid inclusion complex is ziprasidone mesylate complexed with SBECD. 29.A composition of matter comprising a pharmaceutically acceptable salt ofziprasidone and a cyclodextrin, wherein said salt is selected from thetosylate, tartrate, napsylate, besylate, aspartate, tartrate, esylateand mesylate salt; and wherein said cyclodextrin is selected fromγ-cyclodextrin, SBECD and HPBCD.
 30. A composition of matter as definedin claim 29, wherein said composition is an inclusion complex of saidsalt in said cyclodextrin.
 31. A composition as defined in claim 30,wherein said inclusion complex is selected from (1) the tosylate,napsylate, besylate, tartrate, esylate and mesylate salts ofziprasidone, each complexed with SBECD; and (2) the tartrate, esylate,and mesylate salts of ziprasidone, each complexed with HPBCD.
 32. Acomposition as defined in claim 31, wherein said inclusion complex isselected from (1) the tartrate, esylate, and mesylate salts ofziprasidone, each complexed with SBECD; and (2) the tartrate, esylateand mesylate salts of ziprasidone, each complexed with HPBCD.
 33. Acomposition as defined in claim 32, wherein said inclusion complex isselected from ziprasidone mesylate and tartrate, each complexed withSBECD.
 34. A composition as defined in claim 33, wherein said inclusioncomplex is ziprasidone mesylate complexed with SBECD.
 35. A compositionas defined in claim 29, comprising dry mixture of said salt and saidcyclodextrin.
 36. A composition of matter which is an inclusion complexof a pharmaceutically acceptable salt of ziprasidone in a cyclodextrin,wherein said inclusion complex is ziprasidone mesylate complexed withSBECD.